2,2,6,6-Tetramethylpiperidine and its derivatives are important spin traps for labelling biological molecules. This is illustrated in a number of reviews as follows: J. F. W. Keana, Chemical Reviews, 78, 37 (1978); M. Dagonneau et al., Synthesis, 1984, 895; E. G. Rozantsev et al., Synthesis 1971, 401; and E. G. Rozantsev et al., Synthesis, 1971, 190.
Such compounds are also disclosed as inhibitors for preventing the premature polymerization of vinyl monomers as seen in U.S. Pat. No. 5,254,760.
The oxidation of 4-substituted 2,2,6,6-tetramethylpiperidine to the corresponding N-oxyl derivatives is known to occur by a number of different processes. U.S. Pat. No. 4,665,185 describes using tert-butyl hydroperoxide with transition metal catalysts. G. Sosnovsky et al., Z. Naturforsch. 31b, 1376 (1976); J. Zakrzewski, J. Prakt. Chem., 327, 1011 (1985) and E. G. Rozantsev et al., Synthesis, 1971, 190 each teach the use of hydrogen peroxide with sodium tungstate catalyst. U.S. Pat. No. 5,416,215 teaches the use of hydrogen and selected divalent metal salts. M. E. Brik, Tetrahedron Letters, 36, 5519 (1995) teaches the oxidation of secondary amines to nitroxides using Oxone.RTM. (potassium peroxomonosulfate) in aqueous buffered solutions.
E. J. Rauckman et al., Syn. Communications 5(6), 409 (1975) describe inter alia the oxidation of secondary amines to nitroxides using catalytic amounts of sodium tungstate in the presence of acetonitrile, methanol, hydrogen peroxide and sodium bicarbonate at room temperature for two days to give the oxyl compound in a yield of 85%. The required presence of the known sodium tungstate catalyst clearly differentiates the Rauckman process from the instant process where no sodium tungstate is present.
J. Zakrzewski, J. prakt. Chem., 327(6), 1011 (1985) does teach that 30% hydrogen peroxide in the presence of sodium carbonate gives the oxyl compound in a yield of 73%. The Zakrzewski reaction is run at room temperature (there is an exotherm requiring system cooling) and uses a large (three molar) excess of sodium carbonate for a two-day period. This large excess of sodium carbonate is clearly not a catalytic amount.
The instant process differs from that the Zakrzewski process by using only catalytic amounts of carbonate or bicarbonate rather than the large molar excess amount used by Zakrzewski; by running the reaction at elevated tempreatures rather than at room temperature; and by achieving very high yields and conversions of product (up to 99%) in a relatively short period of time (hours) rather than the two days needed for the Zakrzewski process.
It is clear that the instant process involves the use of an environmentally safe and friendly catalyst and avoids the presence of transition metals in waste waters. Sodium bicarbonate and sodium carbonate are easily handled, are economically inexpensive and cause no adverse environmental conditions. The instant process also gives the desired N-oxyl compounds in high yields and conversions without the use for costly and environmetally hazardous transition metals or divalent metal ions.
In a copending application Ser. No. 08/555,822 a process for the preparation of the N-oxyl compound by the oxidation of the corresponding secondary amine using hydrogen peroxide without any catalyst is described.